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Tan X, Han M, Han M, Ren S, Sun Y, Zeng X, Liu X, Yan L, Gabriel A, Yao Q, Kong D, Wang X, Wu J, Wu W. Dimercaprol attenuates oxidative stress-induced damage of retinal ganglion cells in an in vitro and in vivo model of traumatic optic neuropathy. Neuropharmacology 2025:110525. [PMID: 40409536 DOI: 10.1016/j.neuropharm.2025.110525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 05/16/2025] [Accepted: 05/18/2025] [Indexed: 05/25/2025]
Abstract
Traumatic optic neuropathy (TON) is a prevalent form of optic neuropathy, which is a significant cause of irreversible blindness. To date, effective therapeutic interventions for TON are lacking, highlighting the urgent need for the development of new therapeutic drugs. In this study, a compound library comprising 480 Food and Drug Administration (FDA)-approved drugs was screened to identify potentially effective therapeutic drugs for TON. We reported that dimercaprol (DMP), an FDA-approved drug, can reduce L-Glutamic acid (Glu) and hydrogen peroxide (H2O2)-induced injury in a retinal cell line (R28 cell). Our findings further demonstrated that intracellular reactive oxygen species (ROS) and acrolein, a lipid peroxide, are major contributors to apoptosis-induced cell death in vitro. A series of functional assays revealed that DMP can inhibit apoptosis-induced by Glu via scavenging of intracellular ROS and acrolein in R28 cells and primary cortical neurones. Notably, DMP inhibited retinal ganglion cell complex (GCC) thinning and retinal ganglion cell (RGC) loss resulting from optic nerve crush (ONC) injury in vivo. Moreover, DMP effectively eliminated ONC-induced acrolein in the retina and inhibited RGC apoptosis in vivo. In conclusion, intracellular ROS and acrolein play significant roles in RGC loss in TON, and DMP effectively inhibits RGC apoptosis-induced by the oxidative stress pathway in vitro and in vivo. Therefore, DMP has emerged as a potential new therapeutic drug against TON.
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Affiliation(s)
- Xiangpeng Tan
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571199, PR China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction,Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Meiting Han
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China
| | - Mengke Han
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Shuo Ren
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yue Sun
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoqing Zeng
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xin Liu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China
| | - Lin Yan
- The 2nd Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Abekah Gabriel
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Qingqing Yao
- State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction,Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Dulin Kong
- Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571199, PR China
| | - Xiaohui Wang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction,Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
| | - Jianzhang Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, 3 Xueyuan Road, Haikou 571199, PR China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
| | - Wencan Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health), Wenzhou, Zhejiang, 325000, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China; Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction,Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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Song W, Rahimian N, Hasanzade Bashkandi A. GRP78: A new promising candidate in colorectal cancer pathogenesis and therapy. Eur J Pharmacol 2025; 995:177308. [PMID: 39870235 DOI: 10.1016/j.ejphar.2025.177308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/18/2025] [Accepted: 01/23/2025] [Indexed: 01/29/2025]
Abstract
Colorectal cancer (CRC) is a significant global health challenge, marked by varying incidence and mortality rates across different regions. The pathogenesis of CRC involves multiple stages, including initiation, promotion, progression, and metastasis, influenced by genetic and epigenetic factors. The chaperone protein glucose-regulated protein 78 (GRP78), crucial in regulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, plays a pivotal role in CRC pathogenesis. This review discusses the expression profile of GRP78 in CRC, highlighting its potential as a prognostic biomarker and its role in modulating the cellular mechanisms of CRC, including ER response regulation, cell proliferation, migration and invasion. The complex molecular interactions of GRP78 with key signaling pathways such as protein kinase B (Akt), Wnt, protein kinase R-like ER kinase (PERK), vascular endothelial growth factor (VEGF), and Kirsten rat sarcoma virus (Kras) are explored, elucidating its contributions to tumor survival, proliferation, invasion, and chemoresistance. GRP78's involvement in autophagy, glycolysis, and immune regulation further underscores its importance in CRC progression. The review also covers the therapeutic potential of targeting GRP78 in CRC, examining various natural products like curcumin, epigallocatechin gallate (EGCG), and aloe-emodin, which modulate GRP78 expression and activity. Additionally, GRP78's role in mediating resistance to chemotherapeutic agents like 5-fluorouracil (5-FU) and oxaliplatin is discussed, emphasizing its significance in the development of resistance mechanisms in CRC. In conclusion, GRP78 emerges as a central player in CRC pathogenesis and a promising target for therapeutic interventions aimed at improving treatment outcomes and overcoming chemoresistance in colorectal cancer.
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Affiliation(s)
- Wang Song
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.
| | - Neda Rahimian
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
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Xie H, Zhang P, Yang S, Du J, Ren Y, Gao X, Li N, Yang T, Ma Y, Hou X. Myeloid-derived MANF ameliorates ethanol-induced liver injury by enhancing microRNA-223 expression. J Gastroenterol 2025:10.1007/s00535-025-02240-0. [PMID: 40111540 DOI: 10.1007/s00535-025-02240-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/28/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Myeloid cells play a pivotal role in the pathogenesis of alcoholic liver disease (ALD), yet the mechanisms regulating their function and specific contributions to ALD remain inadequately understood. This study aims to investigate the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in the development of ALD. METHODS Myeloid-specific Manf knockout mice and wild-type controls were fed an ethanol-based diet for 10 days, followed by a single ethanol binge. Hepatic MANF levels, along with the correlation between MANF and inflammatory factors in patients with alcoholic hepatitis, were analyzed using the GSE28619 dataset. RESULTS Our study demonstrated that myeloid MANF expression in the liver was upregulated following chronic-plus-binge ethanol exposure. Deletion of the Manf gene in myeloid cells, including neutrophils, exacerbated ethanol-induced liver injury, steatosis, neutrophil infiltration, and reactive oxygen species production. Mechanistic analysis revealed that MANF promotes neutrophil miR-223 expression, a key anti-inflammatory factor in these cells. MANF enhances miR-223 transcription by increasing the expression of the transcription factor PU.1 via p38 mitogen-activated protein kinase signaling. In addition, hepatic MANF levels were elevated in patients with alcoholic hepatitis and correlated with IL-6, IL-1β, and phagocytic oxidase (phox) p47phoxlevels. CONCLUSION Myeloid-derived MANF mitigates alcohol-induced liver injury by upregulating the neutrophilic p38-PU.1-miR-223 axis.
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Affiliation(s)
- Huiyuan Xie
- Department of Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang, China
| | - Pingping Zhang
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Shanru Yang
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Jia Du
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Yan Ren
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Xianxian Gao
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Na Li
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China
| | - Tao Yang
- Department of General Surgery, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Yang Ma
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Xin Hou
- Health Science Center, Ningbo University, Ningbo, 315211, Zhejiang, China.
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Nosalova N, Majirska M, Keselakova A, Martinkova M, Fabianova D, Mirossay A, Pilatova MB, Kello M. Pyrrolidine SS13 induces oxidative stress and autophagy-mediated cell death in colorectal cancer cells. Eur J Pharm Sci 2025; 205:106982. [PMID: 39644983 DOI: 10.1016/j.ejps.2024.106982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/19/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
INTRODUCTION Pyrrolidines, nitrogenous organic compounds, are among the most intensively studied agents because of their antibacterial, antiviral, neurological, and promising antitumor effects. Moreover, many medicinal drugs contain pyrrolidine moiety such as sunitinib (anticancer drug), telaprevir and ombitasvir (antiviral drugs) or ramipril (antihypertensive drug). RATIONALE OF THE STUDY Based on the pro-apoptotic effect of pyrrolidine SS13, this study focuses on the pro-oxidative properties of the tested pyrrolidine SS13 on colorectal cancer cells to deepen the understanding of its mechanisms of action. RESEARCH HYPOTHESIS We hypothesize that SS13 induces oxidative stress and autophagy activation in HCT116 and Caco-2 cell lines, thus contributing to antiproliferative effects. METHODS Flow cytometry, western blot, fluorescence microscopy and qRT-PCR were used to evaluate the effect of pyrrolidine SS13. CONCLUSION AND FUTURE DIRECTIONS Pyrrolidine SS13 induced oxidative stress through the accumulation of reactive oxygen and nitrogen species in both cell lines and the modulation of both superoxide dismutase isoenzymes (SOD1, SOD2). Oxidative stress was also associated with the activation of DNA damage response system and modulation of stress/survival pathways. We demonstrated for the first time that pyrrolidine SS13 is involved in the induction of autophagy accompanied by increased levels of autophagic markers (p-AMPK, p-ULK, LC3I/II and ATG7) and a significant decrease in p62 protein levels in both cell lines. Finally, chloroquine, an inhibitor of autophagy, enhanced cell survival and suppressed the cytotoxic effect of SS13 in HCT116 and Caco-2 cells, indicating that SS13 contributes to autophagy-mediated cell death. Taken together, our results suggest that oxidative stress and autophagy participate in the antiproliferative effect of pyrrolidine SS13 on colorectal cancer cells. Further research using primary cell cultures obtained from different animal tissues as well as performing in vivo experiments is needed to understand these processes in detail and to investigate the potential therapeutic application of new pyrrolidine derivatives.
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Affiliation(s)
- Natalia Nosalova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Monika Majirska
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Alexandra Keselakova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Miroslava Martinkova
- Institute of Chemical Sciences, Department of Organic Chemistry, Faculty of Science, P.J. Šafárik University, Košice, Slovakia.
| | - Dominika Fabianova
- Institute of Chemical Sciences, Department of Organic Chemistry, Faculty of Science, P.J. Šafárik University, Košice, Slovakia.
| | - Andrej Mirossay
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Martina Bago Pilatova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
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Salerno L, Notaro A, Consoli V, Affranchi F, Pittalà V, Sorrenti V, Vanella L, Giuliano M, Intagliata S. Evaluation of the anticancer effects exerted by 5-fluorouracil and heme oxygenase-1 inhibitor hybrids in HTC116 colorectal cancer cells. J Enzyme Inhib Med Chem 2024; 39:2337191. [PMID: 38634597 PMCID: PMC11028004 DOI: 10.1080/14756366.2024.2337191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/25/2024] [Indexed: 04/19/2024] Open
Abstract
Colon cancer remains a clinical challenge in industrialised countries. Its treatment with 5-Flurouracil (5-FU) develops many side effects and resistance. Thus, several strategies have been undertaken so far, including the use of drug cocktails and polypharmacology. Heme oxygenase-1 (HO-1) is an emerging molecular target in the treatment of various cancers. We recently demonstrated that a combination of HO-1 inhibitors with 5-FU and the corresponding hybrids SI1/17, SI1/20, and SI1/22, possessed anticancer activity against prostate and lung cancer cells. In this work, we evaluated these hybrids in a model of colon cancer and found that SI1/22 and the respective combo have greater potency than 5-FU. Particularly, compounds inhibit HO-1 activity in cell lysates, increase ROS and the expression of HO-1, SOD, and Nrf2. Moreover, we observed a decrease of pro-caspase and an increase in cleaved PARP-1 and p62, suggesting apoptotic and autophagic cell death and potential application of these drugs as anticancer agents.
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Affiliation(s)
- Loredana Salerno
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
| | - Antonietta Notaro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Valeria Consoli
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
| | - Federica Affranchi
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
| | - Valeria Pittalà
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
- Department of Molecular Medicine, Arabian Gulf University, Manama, Bahrain
| | - Valeria Sorrenti
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
| | - Luca Vanella
- Department of Drug and Health Sciences, University of Catania, Catania, Italy
| | - Michela Giuliano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Palermo, Italy
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Shan C, Wang Y, Wang Y. The Crosstalk between Autophagy and Nrf2 Signaling in Cancer: from Biology to Clinical Applications. Int J Biol Sci 2024; 20:6181-6206. [PMID: 39664581 PMCID: PMC11628323 DOI: 10.7150/ijbs.103187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/29/2024] [Indexed: 12/13/2024] Open
Abstract
Autophagy is a catabolic process that has been conserved throughout evolution, serving to degrade and recycle cellular components and damaged organelles. Autophagy is activated under various stress conditions, such as nutrient deprivation, viral infections, and genotoxic stress, and operates in conjunction with other stress response pathways to mitigate oxidative damage and maintain cellular homeostasis. One such pathway is the Nrf2-Keap1-ARE signaling axis, which functions as an intrinsic antioxidant defense mechanism and has been implicated in cancer chemoprevention, tumor progression, and drug resistance. Recent research has identified a link between impaired autophagy, mediated by the autophagy receptor protein p62, and the activation of the Nrf2 pathway. Specifically, p62 facilitates Keap1 degradation through selective autophagy, leading to the translocation of Nrf2 into the nucleus, where it transcriptionally activates downstream antioxidant enzyme expression, thus safeguarding cells from oxidative stress. Furthermore, Nrf2 regulates p62 transcription, so a positive feedback loop involving p62, Keap1, and Nrf2 is established, which amplifies the protective effects on cells. This paper aims to provide a comprehensive review of the roles of Nrf2 and autophagy in cancer progression, the regulatory interactions between the Nrf2 pathway and autophagy, and the potential applications of the Nrf2-autophagy signaling axis in cancer therapy.
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Affiliation(s)
- Chan Shan
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yuan Wang
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yin Wang
- Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, 250014, China
- Institute of Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
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Zhang Y, Kang Q, He L, Chan KI, Gu H, Xue W, Zhong Z, Tan W. Exploring the immunometabolic potential of Danggui Buxue Decoction for the treatment of IBD-related colorectal cancer. Chin Med 2024; 19:117. [PMID: 39210410 PMCID: PMC11360867 DOI: 10.1186/s13020-024-00978-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 08/07/2024] [Indexed: 09/04/2024] Open
Abstract
Danggui Buxue (DGBX) decoction is a classical prescription composed of Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), used to enrich blood, and nourish Qi in Chinese medicine, with the potential to recover energy and stimulate metabolism. Chronic inflammation is a risk factor in the development of inflammatory bowel disease (IBD)-related colorectal cancer (CRC). More importantly, AR and ASR have anti-inflammatory and anti-cancer activities, as well as prefiguring a potential effect on inflammation-cancer transformation. We, therefore, aimed to review the immunometabolism potential of DGBX decoction and its components in this malignant transformation, to provide a helpful complement to manage the risk of IBD-CRC. The present study investigates the multifaceted roles of DGBX decoction and its entire components AR and ASR, including anti-inflammation effects, anti-cancer properties, immune regulation, and metabolic regulation. This assessment is informed by a synthesis of scholarly literature, with more than two hundred articles retrieved from PubMed, Web of Science, and Scopus databases within the past two decades. The search strategy employed utilized keywords such as "Danggui Buxue", "Astragali Radix", "Angelicae Sinensis Radix", "Inflammation", and "Metabolism", alongside the related synonyms, with a particular emphasis on high-quality research and studies yielding significant findings. The potential of DGBX decoction in modulating immunometabolism holds promise for the treatment of IBD-related CRC. It is particularly relevant given the heterogeneity of CRC and the growing trend towards personalized medicine, but the precise and detailed mechanism necessitate further in vivo validation and extensive clinical studies to substantiate the immunometabolic modulation and delineate the pathways involved.
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Affiliation(s)
- Yang Zhang
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Qianming Kang
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Luying He
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Ka Iong Chan
- Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, SAR, China
| | - Hui Gu
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Wenjing Xue
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Zhangfeng Zhong
- Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, SAR, China.
| | - Wen Tan
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
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Park J, Purushothaman B, Hong S, Choi M, Jegal KH, Park M, Song JM, Kang KW. GRP78 blockade overcomes acquired resistance to EGFR-tyrosine kinase inhibitors in non-small cell lung cancer. Life Sci 2024; 348:122681. [PMID: 38697281 DOI: 10.1016/j.lfs.2024.122681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/22/2024] [Accepted: 04/28/2024] [Indexed: 05/04/2024]
Abstract
AIMS While significant upregulation of GRP78 has been documented in lung cancer patients, its association with resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains underexamined. Our study aimed to elucidate the functional importance of GRP78 in acquired resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC) and to evaluate its potential as a therapeutic target. MAIN METHODS Immunoblot analysis or flow cytometry was employed to assess several markers for endoplasmic reticulum (ER) stress and apoptosis. Ru(II) complex I and HA15, two known GRP78 inhibitors, were used to evaluate the functional role of GRP78. A Xenograft assay was performed to evaluate the in vivo anti-cancer effects of the GRP78 inhibitors. KEY FINDINGS We validated a significant increase in GRP78 protein levels in HCC827-GR, H1993-GR, and H1993-ER cells. The EGFR-TKI-resistant cells overexpressing GRP78 exhibited significantly higher cell proliferation rates than did their parental counterparts. Notably, GRP78 inhibition resulted in a more profound anti-proliferative and apoptotic response via heightened ER stress and subsequent reactive oxygen species (ROS) production in EGFR-TKI-resistant cell lines compared with their parental cells. In xenograft models implanted with HCC827-GR, both Ru(II) complex I and HA15 significantly suppressed tumor growth and reduced tumor weight. Additionally, we confirmed that GRP78 plays a critical role in the proliferation of H1975, an EGFR-TKI-resistant T790M-mutant cell line, relative to other NSCLC cell lines. SIGNIFICANCE Our findings strongly support targeting of GRP78 as a promising therapeutic strategy for NSCLC patients with acquired resistance to EGFR-TKIs.
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Affiliation(s)
- Jaewoo Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Baskaran Purushothaman
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Sera Hong
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Munkyung Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyung Hwan Jegal
- Department of Korean Medical Classics, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea
| | - Miso Park
- College of Pharmacy, Kangwon National University, Chuncheon, Gangwon-do 24341, Republic of Korea
| | - Joon Myong Song
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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Anastasio C, Donisi I, Del Vecchio V, Colloca A, Mele L, Sardu C, Marfella R, Balestrieri ML, D'Onofrio N. SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells. Cell Mol Biol Lett 2024; 29:80. [PMID: 38811901 PMCID: PMC11134909 DOI: 10.1186/s11658-024-00599-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 05/17/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated. METHODS The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein-protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells. RESULTS Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed. CONCLUSIONS These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms.
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Affiliation(s)
- Camilla Anastasio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Isabella Donisi
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Vitale Del Vecchio
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Luciano Armanni 5, 80138, Naples, Italy
| | - Antonino Colloca
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Luigi Mele
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Luciano Armanni 5, 80138, Naples, Italy
| | - Celestino Sardu
- Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Maria Luisa Balestrieri
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy
| | - Nunzia D'Onofrio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138, Naples, Italy.
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10
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Vaglica A, Maggio A, Badalamenti N, Bruno M, Lauricella M, Occhipinti C, D'Anneo A. Seseli tortuosum L. subsp. tortuosum Essential Oils and Their Principal Constituents as Anticancer Agents. PLANTS (BASEL, SWITZERLAND) 2024; 13:678. [PMID: 38475524 DOI: 10.3390/plants13050678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024]
Abstract
Seseli tortuosum L. subsp. tortuosum, belonging to the Apiaceae family, is a species that grows in Europe, mainly in the Mediterranean regions. The history of its application in traditional medicine highlights its various biological properties. Trying to explore the phytochemistry and pharmacological aspects of this species, the essential oils (EOs) extracted from flowers, stems, and roots of a locally wild accession, never previously investigated, growing in Sicily, Italy, were investigated. The chemical composition of all EOs, obtained by the hydrodistillation method, was evaluated by GC-MS. The most abundant class of all investigated samples was that of monoterpene hydrocarbons (79.98-91.21%) with p-cymene, α-pinene, β-pinene, and β-ocimene as major compounds. These EOs, and their main components, were tested for their possible anticancer activity. Obtained data provided evidence that among the different EOs tested, at the dose of 100 μg/mL, those extracted from stems and roots were particularly effective, already at 24 h of treatment, in reducing the cell viability of 42% and 95%, respectively, in HCT116 colon cancer cell line. These EOs also exerted a remarkable cytotoxic effect that was accompanied by morphological changes represented by cell shrinkage as well as a reduction in residual cell population. Differently, modest effects were found when EOs extracted from flowers were tested in the same experimental conditions. The evaluation of the phytocompounds mainly represented in the EOs extracted from different parts of the plant and tested in a range of concentrations between 20 and 200 μg/mL, revealed that α-pinene, β-pinene, and p-cymene exerted only modest effects on cell viability. Differently, a remarkable effect was found when β-ocimene, the most abundant phytocomponent in EOs from roots, was tested on colon cancer cells. This phytocompound, among those identified in EOs from Seseli tortuosum L. subsp. tortuosum, was found to be the most effective in reducing colon cancer cell viability with IC50 = 64.52 μg/mL at 24 h of treatment. All together, these data suggest that β-ocimene could be responsible for the effects observed in colon cancer cells.
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Affiliation(s)
- Alessandro Vaglica
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
| | - Antonella Maggio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
- NBFC-National Biodiversity Future Center, 90133 Palermo, Italy
| | - Natale Badalamenti
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
- NBFC-National Biodiversity Future Center, 90133 Palermo, Italy
| | - Maurizio Bruno
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, Ed. 17, 90128 Palermo, Italy
- NBFC-National Biodiversity Future Center, 90133 Palermo, Italy
| | - Marianna Lauricella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Institute of Biochemistry, University of Palermo, 90127 Palermo, Italy
| | - Chiara Occhipinti
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Antonella D'Anneo
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
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11
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Kusaczuk M, Ambel ET, Naumowicz M, Velasco G. Cellular stress responses as modulators of drug cytotoxicity in pharmacotherapy of glioblastoma. Biochim Biophys Acta Rev Cancer 2024; 1879:189054. [PMID: 38103622 DOI: 10.1016/j.bbcan.2023.189054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 11/21/2023] [Accepted: 12/08/2023] [Indexed: 12/19/2023]
Abstract
Despite the extensive efforts to find effective therapeutic strategies, glioblastoma (GBM) remains a therapeutic challenge with dismal prognosis of survival. Over the last decade the role of stress responses in GBM therapy has gained a great deal of attention, since depending on the duration and intensity of these cellular programs they can be cytoprotective or promote cancer cell death. As such, initiation of the UPR, autophagy or oxidative stress may either impede or facilitate drug-mediated cell killing. In this review, we summarize the mechanisms that regulate ER stress, autophagy, and oxidative stress during GBM development and progression to later discuss the involvement of these stress pathways in the response to different treatments. We also discuss how a precise understanding of the molecular mechanisms regulating stress responses evoked by different pharmacological agents could decisively contribute to the design of novel and more effective combinational treatments against brain malignancies.
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Affiliation(s)
- Magdalena Kusaczuk
- Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok, Poland.
| | - Elena Tovar Ambel
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, Instituto de Investigación Sanitaria San Carlos IdISSC, 28040 Madrid, Spain
| | - Monika Naumowicz
- Department of Physical Chemistry, Faculty of Chemistry, University of Bialystok, K. Ciolkowskiego 1K, 15-245 Bialystok, Poland
| | - Guillermo Velasco
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, Instituto de Investigación Sanitaria San Carlos IdISSC, 28040 Madrid, Spain.
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12
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Zeng XY, Qiu XZ, Wu JN, Liang SM, Huang JA, Liu SQ. Interaction mechanisms between autophagy and ferroptosis: Potential role in colorectal cancer. World J Gastrointest Oncol 2023; 15:1135-1148. [PMID: 37546557 PMCID: PMC10401467 DOI: 10.4251/wjgo.v15.i7.1135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/28/2023] [Accepted: 04/23/2023] [Indexed: 07/12/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignancy that has the second highest incidence and mortality rate. Although there are many personalized treatment options for CRC, the therapeutic effects are ultimately limited by drug resistance. Studies have aimed to block the initiation and progression of CRC by inducing cell death to overcome this obstacle. Substantial evidence has indicated that both autophagy and ferroptosis play important regulatory roles in CRC. Autophagy, a lysosome-dependent process by which cellular proteins and organelles are degraded, is the basic mechanism for maintaining cell homeostasis. The duality and complexity of autophagy in cancer therapy is a hot topic of discussion. Ferroptosis, a regulated cell death pathway, is associated with iron accumulation-induced lipid peroxidation. The activation of ferroptosis can suppress CRC proliferation, invasion and drug resistance. Furthermore, recent studies have suggested an interaction between autophagy and ferroptosis. Autophagy can selectively degrade certain cellular contents to provide raw materials for ferroptosis, ultimately achieving antitumor and anti-drug resistance. Therefore, exploring the interaction between autophagy and ferroptosis could reveal novel ideas for the treatment of CRC. In this review, we describe the mechanisms of autophagy and ferroptosis, focusing on their roles in CRC and the crosstalk between them.
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Affiliation(s)
- Xin-Ya Zeng
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Xin-Ze Qiu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jiang-Ni Wu
- Department of Pathology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Sheng-Mei Liang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Jie-An Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Shi-Quan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
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13
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Notaro A, Lauricella M, Di Liberto D, Emanuele S, Giuliano M, Attanzio A, Tesoriere L, Carlisi D, Allegra M, De Blasio A, Calvaruso G, D'Anneo A. A Deadly Liaison between Oxidative Injury and p53 Drives Methyl-Gallate-Induced Autophagy and Apoptosis in HCT116 Colon Cancer Cells. Antioxidants (Basel) 2023; 12:1292. [PMID: 37372022 DOI: 10.3390/antiox12061292] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Methyl gallate (MG), which is a gallotannin widely found in plants, is a polyphenol used in traditional Chinese phytotherapy to alleviate several cancer symptoms. Our studies provided evidence that MG is capable of reducing the viability of HCT116 colon cancer cells, while it was found to be ineffective on differentiated Caco-2 cells, which is a model of polarized colon cells. In the first phase of treatment, MG promoted both early ROS generation and endoplasmic reticulum (ER) stress, sustained by elevated PERK, Grp78 and CHOP expression levels, as well as an upregulation in intracellular calcium content. Such events were accompanied by an autophagic process (16-24 h), where prolonging the time (48 h) of MG exposure led to cellular homeostasis collapse and apoptotic cell death with DNA fragmentation and p53 and γH2Ax activation. Our data demonstrated that a crucial role in the MG-induced mechanism is played by p53. Its level, which increased precociously (4 h) in MG-treated cells, was tightly intertwined with oxidative injury. Indeed, the addition of N-acetylcysteine (NAC), which is a ROS scavenger, counteracted the p53 increase, as well as the MG effect on cell viability. Moreover, MG promoted p53 accumulation into the nucleus and its inhibition by pifithrin-α (PFT-α), which is a negative modulator of p53 transcriptional activity, enhanced autophagy, increased the LC3-II level and inhibited apoptotic cell death. These findings provide new clues to the potential action of MG as a possible anti-tumor phytomolecule for colon cancer treatment.
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Affiliation(s)
- Antonietta Notaro
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Marianna Lauricella
- Section of Biochemistry, Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy
| | - Diana Di Liberto
- Section of Biochemistry, Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy
| | - Sonia Emanuele
- Section of Biochemistry, Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy
| | - Michela Giuliano
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Alessandro Attanzio
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Luisa Tesoriere
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Daniela Carlisi
- Section of Biochemistry, Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, 90127 Palermo, Italy
| | - Mario Allegra
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Anna De Blasio
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Giuseppe Calvaruso
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Antonella D'Anneo
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
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14
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Ma DJ, Hwang JS, Noh KB, Oh SH, Kim KW, Shin YJ. Role of NADPH Oxidase 4 in Corneal Endothelial Cells Is Mediated by Endoplasmic Reticulum Stress and Autophagy. Antioxidants (Basel) 2023; 12:1228. [PMID: 37371958 DOI: 10.3390/antiox12061228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/03/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Human corneal-endothelial cells (hCEnCs) are located on the inner layer of the cornea. Injury to CEnCs leads to permanent corneal edema, requiring corneal transplantation. NADPH oxidase 4 (NOX4) has been reported to be implicated in the pathogenesis of CEnCs diseases. Thus, we investigated the role of NOX4 in CEnCs in this study. In an animal study, siRNA for NOX4 (siNOX4) or plasmid for NOX4 (pNOX4) was introduced into the corneal endothelium of rats by electroporation, using a square-wave electroporator (ECM830, Havard apparatus) to decrease or increase the expression of NOX4, respectively, and the rat corneas were cryoinjured through contact with a metal rod of 3 mm diameter frozen in liquid nitrogen for 10 min. The immunofluorescence staining of NOX4 and 8-OHdG showed that the levels of NOX4 and 8-OHdG were decreased in the siNOX4 group compared to the siControl, and increased in the pNOX4 group compared to the pControl at one week after treatment. Without cryoinjury, corneal opacity was more severe, and the density of CEnCs was lower, in pNOX4-treated rats compared to pControl. After cryoinjury, the corneas were more transparent, and the CEnC density was higher, in siNOX4-treated rats. The hCEnCs were cultured and transfected with siNOX4 and pNOX4. The silencing of NOX4 in hCEnCs resulted in a normal cell shape, higher viability, and higher proliferation rate than those transfected with the siControl, while NOX4 overexpression had the opposite effect. NOX4 overexpression increased the number of senescent cells and intracellular oxidative stress levels. NOX4 overexpression increased ATF4 and ATF6 levels, and nuclear translocation of XBP-1, which is the endoplasmic reticulum (ER) stress marker, while the silencing of NOX4 had the opposite effect. Additionally, the mitochondrial membrane potential was hyperpolarized by the silencing of NOX4, and depolarized by NOX4 overexpression. The LC3II levels, a marker of autophagy, were decreased by the silencing of NOX4, and increased by NOX4 overexpression. In conclusion, NOX4 plays a pivotal role in the wound-healing and senescence of hCEnCs, by modulating oxidative stress, ER stress, and autophagy. The regulation of NOX4 may be a potential therapeutic strategy for regulating the homeostasis of CEnCs, and treating corneal-endothelial diseases.
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Affiliation(s)
- Dae Joong Ma
- Department of Ophthalmology, Hallym University Medical Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
| | - Jin Sun Hwang
- Department of Ophthalmology, Hallym University Medical Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
| | - Kyung Bo Noh
- Department of Ophthalmology, Hallym University Medical Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
| | - Sun-Hee Oh
- Department of Ophthalmology, Hallym University Medical Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
| | - Kyoung Wook Kim
- Department of Ophthalmology, Hallym University Medical Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
| | - Young Joo Shin
- Department of Ophthalmology, Hallym University Medical Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
- Hallym BioEyeTech Research Center, College of Medicine, Hallym University, Seoul 07442, Republic of Korea
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15
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Shi H, Ma J, Li Q, Du X, Meng Z, Ru J, Ma C. Four organotin(IV) complexes derived from 2,6-difluoro-3-(propylsulfonamido)benzoic acid: synthesis, structure, in vitro cytostatic activity and antifungal activity evaluation. Inorganica Chim Acta 2023. [DOI: 10.1016/j.ica.2023.121485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2023]
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16
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Celesia A, Franzò M, Di Liberto D, Lauricella M, Carlisi D, D'Anneo A, Notaro A, Allegra M, Giuliano M, Emanuele S. Oncogenic BRAF and p53 Interplay in Melanoma Cells and the Effects of the HDAC Inhibitor ITF2357 (Givinostat). Int J Mol Sci 2023; 24:ijms24119148. [PMID: 37298104 DOI: 10.3390/ijms24119148] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/17/2023] [Accepted: 05/21/2023] [Indexed: 06/12/2023] Open
Abstract
Oncogenic BRAF mutations have been widely described in melanomas and promote tumour progression and chemoresistance. We previously provided evidence that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. Here, we show that oncogenic BRAF localises to the nucleus of these cells, and the compound decreases BRAF levels in both the nuclear and cytosolic compartments. Although mutations in the tumour suppressor p53 gene are not equally frequent in melanomas compared to BRAF, the functional impairment of the p53 pathway may also contribute to melanoma development and aggressiveness. To understand whether oncogenic BRAF and p53 may cooperate, a possible interplay was considered in the two cell lines displaying a different p53 status, being p53 mutated into an oncogenic form in SK-MEL-28 and wild-type in A375 cells. Immunoprecipitation revealed that BRAF seems to preferentially interact with oncogenic p53. Interestingly, ITF2357 not only reduced BRAF levels but also oncogenic p53 levels in SK-MEL-28 cells. ITF2357 also targeted BRAF in A375 cells but not wild-type p53, which increased, most likely favouring apoptosis. Silencing experiments confirmed that the response to ITF2357 in BRAF-mutated cells depends on p53 status, thus providing a rationale for melanoma-targeted therapy.
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Affiliation(s)
- Adriana Celesia
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Marzia Franzò
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Diana Di Liberto
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Marianna Lauricella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Daniela Carlisi
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Antonella D'Anneo
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Antonietta Notaro
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Mario Allegra
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Michela Giuliano
- Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, 90127 Palermo, Italy
| | - Sonia Emanuele
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
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17
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Stefanizzi V, Minutolo A, Valletta E, Carlini M, Cordero FM, Ranzenigo A, Prete SP, Cicero DO, Pitti E, Petrella G, Matteucci C, Marino-Merlo F, Mastino A, Macchi B. Biological Evaluation of Triorganotin Derivatives as Potential Anticancer Agents. Molecules 2023; 28:molecules28093856. [PMID: 37175265 PMCID: PMC10180515 DOI: 10.3390/molecules28093856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/26/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023] Open
Abstract
Metal-derived platinum complexes are widely used to treat solid tumors. However, systemic toxicity and tumor resistance to these drugs encourage further research into similarly effective compounds. Among others, organotin compounds have been shown to inhibit cell growth and induce cell death and autophagy. Nevertheless, the impact of the ligand structure and mechanisms involved in the toxicity of organotin compounds have not been clarified. In the present study, the biological activities of commercially available bis(tributyltin) oxide and tributyltin chloride, in comparison to those of specially synthesized tributyltin trifluoroacetate (TBT-OCOCF3) and of cisplatin, were assessed using cells with different levels of tumorigenicity. The results show that tributyltins were more cytotoxic than cisplatin in all the tested cell lines. NMR revealed that this was not related to the interaction with DNA but to the inhibition of glucose uptake into the cells. Moreover, highly tumorigenic cells were less susceptible than nontumorigenic cells to the nonunique pattern of death induced by TBT-OCOCF3. Nevertheless, tumorigenic cells became sensitive when cotreated with wortmannin and TBT-OCOCF3, although no concomitant induction of autophagy by the compound was detected. Thus, TBT-OCOCF3 might be the prototype of a family of potential anticancer agents.
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Affiliation(s)
- Valeria Stefanizzi
- Department of Chemical Science and Technology, University of Rome "Tor Vergata", 00133 Rome, Italy
- Ph.D. Course in Microbiology, Immunology, Infectious Diseases, and Transplants (MIMIT), University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Antonella Minutolo
- Department of Experimental Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Elena Valletta
- Department of Chemical Science and Technology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Martina Carlini
- Department of Experimental Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Franca M Cordero
- Department of Chemistry Ugo Schiff, University of Florence, 50019 Florence, Italy
| | - Anna Ranzenigo
- Department of Chemistry Ugo Schiff, University of Florence, 50019 Florence, Italy
| | | | - Daniel Oscar Cicero
- Department of Chemical Science and Technology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Erica Pitti
- Department of Chemical Science and Technology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Greta Petrella
- Department of Chemical Science and Technology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Claudia Matteucci
- Department of Experimental Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Francesca Marino-Merlo
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Antonio Mastino
- The Institute of Translational Pharmacology, CNR, 00133 Rome, Italy
| | - Beatrice Macchi
- Department of Chemical Science and Technology, University of Rome "Tor Vergata", 00133 Rome, Italy
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18
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Wu J, Wang D, Zhou J, Li J, Xie R, Li Y, Huang J, Liu B, Qiu J. Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells. Phytother Res 2023; 37:310-328. [PMID: 36086867 DOI: 10.1002/ptr.7614] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 07/11/2022] [Accepted: 08/20/2022] [Indexed: 01/19/2023]
Abstract
Prostate cancer (PCa) is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC) with limited therapies. Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti-tumor capacity in various cancers. Our results showed that GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells. In addition, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA. Moreover, the activation of JNK pathway and the induction of apoptosis and autophagy triggered by GNA were attenuated by JNK inhibitor SP600125. We also found that GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. Meanwhile, suppressing ER stress with 4-phenylbutyric acid (4-PBA) markedly blocked the activation of JNK pathway induced by GNA. Further research indicated that ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA. Furthermore, NAC and 4-PBA significantly reversed GNA-triggered apoptosis and autophagy. Finally, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo. In conclusion, the present study revealed that GNA induced apoptosis and autophagy through ROS-mediated ER stress via JNK signaling pathway in PCa cells. Thus, GNA might be a promising therapeutic drug against PCa.
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Affiliation(s)
- Jianjian Wu
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
| | - Dejuan Wang
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
| | - Jiuyao Zhou
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Juntao Li
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
| | - Ruoxin Xie
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
| | - Yiyuan Li
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
| | - Jiayu Huang
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
| | - Bihao Liu
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China.,Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
| | - Jianguang Qiu
- Department of Urology, The Sixth Affiliated Hospital of Sun Yat-Sen Univerisity, Guangzhou, China
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Yang R, Ma S, Zhuo R, Xu L, Jia S, Yang P, Yao Y, Cao H, Ma L, Pan J, Wang J. Suppression of endoplasmic reticulum stress-dependent autophagy enhances cynaropicrin-induced apoptosis via attenuation of the P62/Keap1/Nrf2 pathways in neuroblastoma. Front Pharmacol 2022; 13:977622. [PMID: 36188599 PMCID: PMC9523313 DOI: 10.3389/fphar.2022.977622] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/05/2022] [Indexed: 12/03/2022] Open
Abstract
Autophagy has dual roles in cancer, resulting in cellular adaptation to promote either cell survival or cell death. Modulating autophagy can enhance the cytotoxicity of many chemotherapeutic and targeted drugs and is increasingly considered to be a promising cancer treatment approach. Cynaropicrin (CYN) is a natural compound that was isolated from an edible plant (artichoke). Previous studies have shown that CYN exhibits antitumor effects in several cancer cell lines. However, it anticancer effects against neuroblastoma (NB) and the underlying mechanisms have not yet been investigated. More specifically, the regulation of autophagy in NB cells by CYN has never been reported before. In this study, we demonstrated that CYN induced apoptosis and protective autophagy. Further mechanistic studies suggested that ER stress-induced autophagy inhibited apoptosis by activating the p62/Keap1/Nrf2 pathways. Finally, in vivo data showed that CYN inhibited tumour growth in xenografted nude mice. Overall, our findings suggested that CYN may be a promising candidate for the treatment of NB, and the combination of pharmacological inhibitors of autophagy may hold novel therapeutic potential for the treatment of NB. Our paper will contribute to the rational utility and pharmacological studies of CYN in future anticancer research.
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Affiliation(s)
- Randong Yang
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Shurong Ma
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Ran Zhuo
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Lingqi Xu
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Siqi Jia
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Pengcheng Yang
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Ye Yao
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Haibo Cao
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Liya Ma
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Jian Pan
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
- *Correspondence: Jian Pan, ; Jian Wang,
| | - Jian Wang
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
- *Correspondence: Jian Pan, ; Jian Wang,
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20
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Celesia A, Notaro A, Franzò M, Lauricella M, D’Anneo A, Carlisi D, Giuliano M, Emanuele S. The Histone Deacetylase Inhibitor ITF2357 (Givinostat) Targets Oncogenic BRAF in Melanoma Cells and Promotes a Switch from Pro-Survival Autophagy to Apoptosis. Biomedicines 2022; 10:biomedicines10081994. [PMID: 36009541 PMCID: PMC9405675 DOI: 10.3390/biomedicines10081994] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Histone deacetylase inhibitors (HDACI) are epigenetic compounds that have been widely considered very promising antitumor agents. Here, we focus on the effects of the pan-HDAC inhibitor ITF2357 (Givinostat) in comparison with SAHA (Vorinostat) in melanoma cells bearing BRAF V600E oncogenic mutation. Our results indicate both ITF2357 and SAHA dose-dependently reduce the viability of BRAF-mutated SK-MEL-28 and A375 melanoma cells. The comparison of IC50 values revealed that ITF2357 was much more effective than SAHA. Interestingly, both inhibitors markedly decreased oncogenic BRAF protein expression levels, ITF2357 being the most effective compound. Moreover, the BRAF decrease induced by ITF2357 was accompanied by a decrease in the level of phospho-ERK1/2. The inhibitor of upstream MEK activity, U0126, reduced ERK1/2 phosphorylation and dramatically potentiated the antitumor effect of ITF2357, exacerbating the reduction in the BRAF level. ITF2357 stimulated an early pro-survival autophagic response, which was followed by apoptosis, as indicated by apoptotic markers evaluation and the protective effects exerted by the pan-caspase inhibitor z-VADfmk. Overall, our data indicate for the first time that ITF2357 targets oncogenic BRAF in melanoma cells and induces a switch from autophagy to classic apoptosis, thus representing a possible candidate in melanoma targeted therapy.
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Affiliation(s)
- Adriana Celesia
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Antonietta Notaro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy
| | - Marzia Franzò
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Marianna Lauricella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Antonella D’Anneo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy
| | - Daniela Carlisi
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
| | - Michela Giuliano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy
- Correspondence: (M.G.); (S.E.)
| | - Sonia Emanuele
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), Biochemistry Building, University of Palermo, 90127 Palermo, Italy
- Correspondence: (M.G.); (S.E.)
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21
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Yu S, Li C, Fan S, Wang J, Liang L, Hong M. Three organotin(IV) Schiff-base carboxylates: Synthesis, structural characterization and in vitro cytotoxicity against cis-platin-resistent cancer cells. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.132585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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22
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yingBai Y, meiCheng Y, Wang W, Yang L, Yang Y. In vivo and in vitro studies of Alloimperatorin induced autophagy in cervical cancer cells via reactive oxygen species pathway. Bioengineered 2022; 13:14299-14314. [PMID: 36708242 PMCID: PMC9995126 DOI: 10.1080/21655979.2022.2084243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/19/2022] [Accepted: 05/25/2022] [Indexed: 01/29/2023] Open
Abstract
Alloimperatorin (Alloi) has been shown to have anti-proliferative effects in our previous studies. we aimed to investigate whether Alloimperatorin induces autophagy through the reactive oxygen species (ROS) pathway and anticancer activity in vivo. The anti-proliferative effect of Alloimperatorin was evaluated using a cell counting kit (CCK-8 kit). Apoptosis was detected using flow cytometry. Confocal microscopy, immunofluorescence, and mRFP-GFP-LC3 lentivirus transfection were used to verify autophagy. Electron microscopy detection of autophagosomes was induced by Alloimperatorin. Western blotting was used to detect autophagy proteins in HeLa and SiHa cells. A xenograft model was used to monitor the inhibitory effect of Alloimperatorin on tumor growth in nude mice. The results showed that Alloimperatorin induced ROS production and inhibited the proliferation of HeLa and SiHa cells. Furthermore, Alloimperatorin increased the apoptosis rate in HeLa and SiHa cells. Confocal microscopy fluorescence indicated that Alloimperatorin increased autophagy fluorescence of HeLa and SiHa cells. mRFP-GFP-LC3 lentivirus transfection and electron microscopy demonstrated that Alloimperatorin increased autophagy in HeLa and SiHa cells. Western blotting showed that Alloimperatorin induced the expression of autophagy proteins in HeLa and SiHa cells. However, N-acetylcysteine reversed the autophagy. These results demonstrate that Alloimperatorin can induce autophagy in HeLa and SiHa cells through the ROS pathway. In vivo xenograft experiments showed that Alloimperatorin could inhibit tumor growth in nude mice. Alloimperatorin is expected to be an effective new drug for cervical cancer treatment.Abbreviations: ROS, reactive oxygen species; Alloi, Alloimperatorin; CCK-8, Cell Counting Kit-8; NAC, N-acetyl-L-cysteine; DCFH-DA, 2,7-dichlorodihydrofluorescein diacetate; OD, optical density; PBS, phosphate buffer solution; BCA, bicinchoninic acid; DAPI, 4,6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.
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Affiliation(s)
- Ying yingBai
- The First Clinical Medical College of Lanzhou University, Lanzhou, PR China
| | - Yue meiCheng
- The First Clinical Medical College of Lanzhou University, Lanzhou, PR China
| | - Wenhua Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, PR China
| | - Lijuan Yang
- The First Clinical Medical College of Lanzhou University, Lanzhou, PR China
| | - Yongxiu Yang
- The First Clinical Medical College of Lanzhou University, Lanzhou, PR China
- Department of Obstetrics and Gynecology, First Hospital of Lanzhou University, Lanzhou, PR China
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Bortezomib potentiates the antitumor effect of tributyltin(IV) ferulate in colon cancer cells exacerbating ER stress and promoting apoptosis. Inorganica Chim Acta 2022. [DOI: 10.1016/j.ica.2022.120929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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24
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Bio-Waste Products of Mangifera indica L. Reduce Adipogenesis and Exert Antioxidant Effects on 3T3-L1 Cells. Antioxidants (Basel) 2022; 11:antiox11020363. [PMID: 35204243 PMCID: PMC8869144 DOI: 10.3390/antiox11020363] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/04/2022] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
Abstract
Several studies highlighted the beneficial value of natural compounds in the prevention and treatment of obesity. Here, we investigated the anti-obesity effects of extracts of peel and seed of mango (Mangifera indica L.) cultivated in Sicily (Italy) in 3T3-L1 cells. Mango Peel (MPE) and Mango Seed (MSE) extracts at a 100 µg/mL concentration significantly reduced lipid accumulation and triacylglycerol contents during 3T3-L1 adipocyte differentiation without toxicity. HPLC-ESI-MS analysis showed that both the extracts contain some polyphenolic compounds that can account for the observed biological effects. The anti-adipogenic effect of MPE and MSE was the result of down-regulation of the key adipogenic transcription factor PPARγ and its downstream targets FABP4/aP2, GLUT4 and Adipsin, as well SREBP-1c, a transcription factor which promotes lipogenesis. In addition, both MPE and MSE significantly activated AMPK with the consequent inhibition of Acetyl-CoA-carboxylase (ACC) and up-regulated PPARα. The addition of compound C, a specific AMPK inhibitor, reduced the effects of MPE and MSE on AMPK and ACC phosphorylation, suggesting a role of AMPK in mediating MPE and MSE anti-lipogenic effects. Notably, MPE and MSE possess an elevated radical scavenging activity, as demonstrated by DPPH radical scavenging assay, and reduced ROS content produced during adipocyte differentiation. This last effect could be a consequence of the increase in the antioxidant factors Nrf2, MnSOD and HO-1. In conclusion, MPE and MSE possesses both anti-adipogenic and antioxidant potential, thus suggesting that the bio-waste products of mango are promising anti-obesity natural compounds.
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25
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Morana O, Wood W, Gregory CD. The Apoptosis Paradox in Cancer. Int J Mol Sci 2022; 23:ijms23031328. [PMID: 35163253 PMCID: PMC8836235 DOI: 10.3390/ijms23031328] [Citation(s) in RCA: 213] [Impact Index Per Article: 71.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/01/2023] Open
Abstract
Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)-including phagocytes and viable tumour cells-and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with "double-edged" consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.
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26
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Kaur R, Sood A, Lang DK, Arora R, Kumar N, Diwan V, Saini B. Natural Products as Sources of Multitarget Compounds: Advances in the Development of Ferulic Acid as Multitarget Therapeutic. Curr Top Med Chem 2022; 22:347-365. [PMID: 35040403 DOI: 10.2174/1568026622666220117105740] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/25/2021] [Accepted: 12/27/2021] [Indexed: 11/22/2022]
Abstract
Nature has provided therapeutic substances for millennia, with many valuable medications derived from plant sources. Multitarget drugs become essential in the management of various disorders including hepatic disorders, neurological disorders, diabetes, and carcinomas. Ferulic acid is a significant potential therapeutic agent, which is easily available at low cost, possesses a low toxicity profile, and has minimum side effects. Ferulic acid exhibits various therapeutic actions by modulation of various signal transduction pathways such as Nrf2, p38, and mTOR. The actions exhibited by ferulic acid include anti-apoptosis, antioxidant, anti-inflammatory, antidiabetic, anticarcinogenic, hepatoprotection, cardioprotection, activation of transcriptional factors, expression of genes, regulation of enzyme activity, and neuroprotection, which further help in treating various pathophysiological conditions such as cancer, skin diseases, brain disorders, diabetes, Parkinson's disease, Alzheimer's disease, hypoxia, hepatic disorders, H1N1 flu, and viral infections. The current review focuses on the significance of natural products as sources of multitarget compounds and a primary focus has been made on ferulic acid and its mechanism, role, and protective action in various ailments.
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Affiliation(s)
- Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Ankita Sood
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | | | - Rashmi Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neeraj Kumar
- National Institute of Pharmaceutical Education and Research, Hyderabad, India
| | - Vishal Diwan
- Centre for Chronic Disease, The University of Queensland, Australia
| | - Balraj Saini
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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27
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Chen J, Qiu M, Zhang S, Li B, Li D, Huang X, Qian Z, Zhao J, Wang Z, Tang D. A calcium phosphate drug carrier loading with 5-fluorouracil achieving a synergistic effect for pancreatic cancer therapy. J Colloid Interface Sci 2022; 605:263-273. [PMID: 34332405 DOI: 10.1016/j.jcis.2021.07.080] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/29/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022]
Abstract
Calcium based biomaterials were widely used for drug delivery application due to their biodegradability, biocompatibility, and high drug loading capacity. Herein, amino-capped polyamidoamine (PAMAM) dendrimer was applied as a macromolecular template to form amino-modified calcium phosphate hollow sphere (CaPO-NH2). After loading with 5-fluorouracil (5Fu), this system performed synergistic cancer chemotherapy. In this study, the 5Fu/CaPO-NH2 particles could be efficiently uptaken by cancer cells, and then decompose into Ca2+ and release 5Fu drug in the cytoplasm; therefore calcium overload and reactive oxygen species (ROS) accumulation were found in PSN1 cells that could induce cell membrane damage and elicit cell apoptosis through a series of biochemical reactions including endoplasmic reticulum stress, lipid peroxidation and mitochondrial apoptosis. In the PSN1 pancreatic cancer xenograft model, the 5Fu/CaPO-NH2 system performed high tumor inhibition via chemotherapy and calcium overload induced apoptosis. Comparingly, the normal cells and organs were insensitive to this synergistic therapy, which indicated the well biocompatibility of delivery system. Thus, this study provided a promising CaPO-NH2 drug delivery platform for enhanced 5Fu chemotherapeutic effect.
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Affiliation(s)
- Junzong Chen
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Miaojuan Qiu
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Shiqiang Zhang
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Binbin Li
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Dong Li
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Xiuyu Huang
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Zhirong Qian
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China
| | - Jing Zhao
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China.
| | - Zhiyong Wang
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China; School of Materials Science and Engineering, Center for Functional Biomaterials, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Guangzhou Key Laboratory of Flexible Electronic Materials and Wearable Devices, Sun Yat-sen University, Guangzhou 510275, PR China.
| | - Di Tang
- The Seventh Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen 518107, China.
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Emanuele S, Celesia A, D’Anneo A, Lauricella M, Carlisi D, De Blasio A, Giuliano M. The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19. Int J Mol Sci 2021; 22:7963. [PMID: 34360732 PMCID: PMC8348506 DOI: 10.3390/ijms22157963] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 01/08/2023] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively.
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Affiliation(s)
- Sonia Emanuele
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy; (A.C.); (M.L.); (D.C.)
| | - Adriana Celesia
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy; (A.C.); (M.L.); (D.C.)
| | - Antonella D’Anneo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Biochemistry Building, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy; (A.D.); (A.D.B.); (M.G.)
| | - Marianna Lauricella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy; (A.C.); (M.L.); (D.C.)
| | - Daniela Carlisi
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy; (A.C.); (M.L.); (D.C.)
| | - Anna De Blasio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Biochemistry Building, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy; (A.D.); (A.D.B.); (M.G.)
| | - Michela Giuliano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), Biochemistry Building, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy; (A.D.); (A.D.B.); (M.G.)
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Redox Imbalance and Mitochondrial Release of Apoptogenic Factors at the Forefront of the Antitumor Action of Mango Peel Extract. Molecules 2021; 26:molecules26144328. [PMID: 34299603 PMCID: PMC8303932 DOI: 10.3390/molecules26144328] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/09/2021] [Accepted: 07/15/2021] [Indexed: 12/19/2022] Open
Abstract
Today, an improved understanding of cancer cell response to cellular stress has become more necessary. Indeed, targeting the intracellular pro-oxidant/antioxidant balance triggering the tumor commitment to cell demise could represent an advantageous strategy to develop cancer-tailored therapies. In this scenario, the present study shows how the peel extract of mango-a tropical fruit rich in phytochemicals with nutraceutical properties-can affect the cell viability of three colon cancer cell lines (HT29, Caco-2 and HCT116), inducing an imbalance of cellular redox responses. By using hydro-alcoholic mango peel extract (MPE), we observed a consistent decline in thiol group content, which was accompanied by upregulation of MnSOD-a mitochondrial scavenger enzyme that modulates the cellular response against oxidative damage. Such an effect was the consequence of an early production of mitochondrial superoxide anions that appeared after just 30 min of exposure of colon cancer cells to MPE. The effect was accompanied by mitochondrial injury, consisting of the dissipation of mitochondrial membrane potential and a decrease in the level of proteins localized in the mitochondrial membrane-such as voltage-dependent anion-selective channel (VDAC1), mitofilin, and some members of Bcl-2 family proteins (Mcl-1, Bcl-2 and Bcl-XL)-with the mitochondrial release of apoptogenic factors (cytochrome C and AIF). The analysis of the cytotoxic effects exerted by the different constituents of MPE (gallic acid, mangiferin, citric acid, quinic acid, pentagalloyl glucose, and methyl gallate) allowed us to identify those phytochemicals responsible for the observed anticancer effects, sustaining their future employment as chemopreventive or therapeutic agents.
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Mirzaei S, Hushmandi K, Zabolian A, Saleki H, Torabi SMR, Ranjbar A, SeyedSaleh S, Sharifzadeh SO, Khan H, Ashrafizadeh M, Zarrabi A, Ahn KS. Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies. Molecules 2021; 26:2382. [PMID: 33921908 PMCID: PMC8073650 DOI: 10.3390/molecules26082382] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.
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Affiliation(s)
- Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran 1477893855, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran 1417466191, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Hossein Saleki
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Seyed Mohammad Reza Torabi
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Adnan Ranjbar
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - SeyedHesam SeyedSaleh
- Student Research Committee, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Seyed Omid Sharifzadeh
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1477893855, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, Istanbul 34956, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey
| | - Kwang-Seok Ahn
- Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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Tullio V, Gasperi V, Catani MV, Savini I. The Impact of Whole Grain Intake on Gastrointestinal Tumors: A Focus on Colorectal, Gastric, and Esophageal Cancers. Nutrients 2020; 13:E81. [PMID: 33383776 PMCID: PMC7824588 DOI: 10.3390/nu13010081] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/22/2020] [Accepted: 12/25/2020] [Indexed: 02/08/2023] Open
Abstract
Cereals are one of staple foods in human diet, mainly consumed as refined grains. Nonetheless, epidemiological data indicate that whole grain (WG) intake is inversely related to risk of type 2 diabetes, cardiovascular disease, and several cancer types, as well as to all-cause mortality. Particularly responsive to WG positive action is the gastrointestinal tract, daily exposed to bioactive food components. Herein, we shall provide an up-to-date overview on relationship between WG intake and prevention of gastrointestinal tumors, with a particular focus on colorectal, stomach, and esophagus cancers. Unlike refined counterparts, WG consumption is inversely associated with risk of these gastrointestinal cancers, most consistently with the risk of colorectal tumor. Some WG effects may be mediated by beneficial constituents (such as fiber and polyphenols) that are reduced/lost during milling process. Beside health-promoting action, WGs are still under-consumed in most countries; therefore, World Health Organization and other public/private stakeholders should cooperate to implement WG consumption in the whole population, in order to reach nutritionally effective intakes.
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Dual Function Molecules and Processes in Cell Fate Decision: A Preface to the Special Issue. Int J Mol Sci 2020; 21:ijms21249601. [PMID: 33339424 PMCID: PMC7766797 DOI: 10.3390/ijms21249601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 12/04/2020] [Indexed: 11/17/2022] Open
Abstract
A lot of water has passed under the bridge since 1999, when C [...].
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